Carbon monoxide (CO) gas is poisonous in high concentrations. However, it is now recognized as an important signaling molecule (Verma et al., Science 259:381–384, 1993). It has also been suggested that carbon monoxide acts as a neuronal messenger molecule in the brain (Id.) and as a neuro-endocrine modulator in the hypothalamus (Pozzoli et al., Endocrinology 735:2314–2317, 1994). Like nitric oxide (NO), carbon monoxide is a smooth muscle relaxant (Utz et al., Biochem Pharmacol. 47:195–201, 1991; Christodoulides et al., Circulation 97:2306–9, 1995) and inhibits platelet aggregation (Mansouri et al., Thromb Haemost. 48:286–8, 1982). Inhalation of low levels of CO has been shown to have anti-inflammatory effects in some models.
Islet cell transplantation is a viable treatment for the amelioration of type I diabetes (Lacy et al., Annu. Rev. Immunol., 2:183–98, 1984; Weir et al., J. Am. Optom. Assoc. 69:727–32, 2000; Berney et al., Langenbechs Arch. Surg. 385: 378–8, 2000; Shapiro et al., N Engl. J. Med., 343:230–8, 2000). However, the processes of clinical islet transplantation are made difficult by a number of factors. One factor is primary nonfunction (PNF) of the graft. Another is the need for high numbers of donor islets needed for a successful reversal of diabetes (Shapiro et al., N Engl. J. Med., 343:230–8, 2000). Both situations reflect the same pathophysiology: the substantial cell loss in the graft within the first weeks after transplantation. After transplantation, islets suffer a variety of stress factors such as hypoxia before secondary vascularization (Carlsson et al., Diabetes 47:1027–32, 1998) and exposure to pro-inflammatory cytokines and free radicals released from macrophages in the microenvironment of the transplant (Rabinovitch et al., Diabetes 48:1223–9, 1999; Kaufman et al., J Exp Med. 772:291–302, 1990; Corbett et al., Proc. Natl. Acad. Sci USA 90:1731–5, 1993) and from resident islet macrophages (Mandrup-Poulsen et al., J. Immunol. 739:4077–82, 1987; Arnush et al., J. Clin Invest. 702:516–26, 1998). The toxic effects of immunosuppressive drugs as well as rejection (Weir et al., Diabetes 46:1247–56, 1997) also contribute to islet cell loss. The existence of PNF after experimental syngeneic islet transplantation (Nagata et al., Transplant Proc. 22:855–6, 1990; Arita et al., Transplantation 65:1429–33, 1998) indicates that non-specific inflammation plays a major role in this scenario.
Survival of a transplanted organ is thought to relate mainly to the success of immunosuppression, in terms of blocking the immune response that leads to graft rejection. However, it has previously been shown that transplanted organs can protect themselves from vascular injury leading to rejection through the expression of“protective genes” (see, e.g., Bach et al., Nature Med. 3:196–202 (1997); and Soares et al., Nat Med. 4:1073–1077, 1998). One such gene, heme oxygenase-1 (HO-1) catabolizes heme into biliverdin, free iron and CO (Tenhunen et al., Proc Natl Acad Sci USA 61:748–755, 1968).
Endothelial cells (ECs) lining blood vessels maintain blood flow, allowing the continuous traffic of plasma and cellular constituents between blood and parenchymal tissues. To accomplish this function, ECs must promote a certain level of vasorelaxation and inhibit leukocyte adhesion as well as coagulation and thrombosis. However, when ECs are exposed to proinflammatory stimuli, they become “activated” and promote vasoconstriction, leukocyte adhesion and activation, and coagulation and thrombosis. These functional changes are due to the expression by activated ECs of a series of proinflammatory genes encoding adhesion molecules, cytokines/chemokines, and costimulatory and procoagulant molecules. Unfettered EC activation, as during acute and chronic inflammation, can lead to EC injury and apoptosis. EC apoptosis is a prominent feature associated with acute and/or chronic inflammation such as it occurs during hyperoxia, endotoxic shock, arteriosclerosis, ischemia reperfusion injury, and acute or chronic graft rejection.